Breast cancer is the most common cancer among women both in the United States and globally. Current screening programs are not completely successful in reducing breast cancer mortality. There is a great need to continue searching for novel non-invasive biomarkers for breast cancer detection and screening. A paradigm shift is to focus on biomarkers that identify aggressive form of breast cancer, rather than lumping all breast cancer together. MicroRNAs represent a class of emerging and attractive cancer biomarkers because they maintain in a protected state in serum and plasma, have tissue-specific expression profiles, and can be uniformly amplified and quantified. In this application, we propose to systematically identify microRNAs in serum that are differentially expressed between 30 triple-negative breast cancers, 30 other breast cancers, and 40 matched controls, followed by a replication study in an independent sample of 60 cases and 40 controls. To prioritize and select putative microRNAs, we will also examine the concordance of microRNA levels in the serum and breast tissues of breast cancer patients, and explore their biologic relevance using bioinformatics approach and experimental validation. All biospecimens have been collected in previous breast cancer studies. This study has several innovative aspects including its systematic unbiased approach, focusing on aggressive tumor subtypes, and integrated approach for assessing biological relevant miRNAs using ethnically diverse population. This study is directly translational and will open the door to new strategy of breast cancer prevention and control. PUBLIC HEALTH RELEVANCE: Breast cancer is the most common cancer among women and it is now widely accepted that breast cancer consists of several subtypes with triple-negative breast cancers having the worst clinical outcomes and being difficult to be detected using current screening methods. We propose to measure a class of small RNAs (microRNA) in blood of triple-negative breast cancer patients, other breast cancer patients, and healthy controls. Our long-term goal is to identify novel biomarkers for detection and screening breast cancer, especially triple-negative breast cancer.